The pathologic hallmarks of Alzheimer's disease (AD) are intra- and extra- cellular deposits of proteins which are thought to be causally related to the neuronal dysfunction associated with progressive dementia. Accumulated polypeptides whose turnover is slow are subject to nonenzymatic glycation with the ultimate formation of advanced glycation end products (AGEs); an heterogeneous group of structures which form cross links, interact with the Receptor for AGE (RAGE), and generate reactive oxygen intermediates (R01s). Recent findings from my and other laboratories have shown that intraneuronal paired helical filament (PHF) tau and extracellular deposits of amyloid-Beta peptide (ABeta) in the vasculature and senile plaques are present in AD brain in an AGE-modified form. Furthermore, expression of RAGE is enhanced in neurons bearing PHF tau and in vasculature from AD. My hypothesis is that AGEs associated with PHF tau and AGE-modification of A- beta (in the latter case via RAGE) promote interaction with neurons, microglia, and vessel wall elements, in each case generating R01s and feeding into a final common pathway of oxidant stress whereby cellular functions are perturbed, gene expression is modified, and there is increased release of A-beta. The specific aims are (I) to determine if AGEs in PHFs and AGE-modified recombinant tau induce cellular oxidant stress with NF-kB activation and expression of Interleukin (IL)-6, and enhance release of amyloidogenic A-beta peptides; and (ii) if AGE-A-beta and A-beta isolated from AD brain demonstrate enhanced interaction with neurons, microglia, endothelium and smooth muscle via RAGE, and if such interactions lead to oxidant stress with generation of IL-6, changes in A- beta processing and modulation of other cellular properties.